This invention relates to a compound for replacing or reconstructing rigid or semi-rigid living tissue. More particularly, the present invention relates to compositions comprising poly(propylene fumarate) cross linked with poly(ethylene glycol) and methods for making these compositions.
In the field of tissue engineering, degradable biomaterials usually serve as a scaffold to provide mechanical support and a matrix for the ingrowth of new tissue. As new tissue forms on the scaffold, the biomaterial degrades until it is entirely dissolved. The degradation products are eliminated through the body""s natural pathways, such as metabolic processes.
One example of the use of such biomaterials is as a temporary bone replacement. It is often desired to replace or reconstruct all or a portion of a living bone, such as when a bone has been broken or has been resected as a result of a bone tumor. In these instances, the missing bone can be replaced with a mechanical device, such as a pin, plate or the like, or it can be replaced with an implant that is designed to more closely resemble the original bone itself. Often these implants comprise biodegradable polymeric compounds or parts made from such compounds. It is contemplated that bone tissue will grow back into the pores of the implant and will gradually replace the entire implant as the implant itself is gradually degraded in the in vivo environment. For obvious reasons then, such implants should be biocompatible and non-toxic.
Poly(propylene fumarate) (PPF) is one such polymer. Poly(propylene fumarate) (hereinafter xe2x80x9cPPFxe2x80x9d) is an unsaturated linear polyester that degrades in the presence of water into propylene glycol and fulmaric acid, degradation products that are easily cleared from the human body by normal metabolic processes. Because the fumarate double bonds in PPF are reactive and cross link at low temperatures, PPF has potential to be an effective in situ polymerizable biomaterial. The high mechanical strength of cured PPF matrices and their ability to be cross linked in situ makes them especially suitable for orthopedic application. Another advantage of cured PPF matrices is that they biodegrade into non-toxic propylene glycol and fumaric acid. On the basis of these unique properties, PPF has been formulated as bone cement, an orthopaedic scaffold for bone tissue regeneration, and a drug delivery system.
Several PPF-based formulation methods have been evaluated by varying such parameters as the molecular weight of PPF and the choice of cross linking reagents. For example, U.S. Pat. No. 5,733,951 discloses a composite mixture incorporating P(PF), a cross linking monomer (N-vinyl pyrrolidone), a porogen (sodium chloride), and a particulate phase (xcex2-tricalcium phosphate) that can be injected or inserted into skeletal defects of irregular shape or size.
The properties of some PPF composites can be tailored for specific applications by varying different parameters, including crosslinking density and molecular weight of PPF. PPF composite formulations can include a porogen such as NaCl for initial porosity and a particulate ceramic such as xcex2-TCP for mechanical reinforcement and increased osteoconductivity. PPF composite formulations can also include a vinyl monomer such as N-vinyl pyrrolidone, which serves as a crosslinking reagent. However, because this monomer is toxic, any unreacted amount during polymerization in situ may present a problem.
Poly(ethylene glycol), (PEG), is a hydrophilic polyether that has received much attention for use in biomaterials because low molecular weight PEG is passively excreted by the body. PEG has also been covalently bound to polyesters in an effort to increase polyester biocompatibility. The use of acrylated PEG as a nontoxic crosslinking reagent to produce polymer networks with acrylated poly(lactic acid) has been reported. To date however, PPF-based polymers cross-linked with PEG have not been made. Hence, it remains desirable to provide a poly(propylene fumarate) cross linked with poly(ethylene glycol) and a method for making it. The method for making would preferably include a method for controlling the mechanical properties of the resulting polymer.
The present invention comprises new, injectable biodegradable polymer composites based on PPF cross linked with biocompatible PEG-DMA and, if desired, xcex2-TCP. The invention further provides the ability to control the crosslinking characteristics of the polymerizing composites and the mechanical properties of cross linked composites by varying the xcex2-TCP content and the double bond ratio of PEG-DMA/PPF. The PPF/PEG-DMA networks produced according to the present invention have clinically acceptable gel times, cross-linking temperature increases of less than 2xc2x0 C., and are suitable for use as injectable, biodegradable carriers for cell transplantation or drug delivery.
As used herein, the term xe2x80x9cnetworkxe2x80x9d refers to polymeric molecules that have been cross linked so as to effectively form a continuous molecule. The term xe2x80x9cgelxe2x80x9d is sometimes used to refer to the same type of cross linked systems.